Is there an Exposure–Response Relationship for Nivolumab in Real-World NSCLC Patients?
Abstract
:1. Introduction
2. Results
2.1. Study Population
2.2. Pharmacokinetic Variability
2.3. Exposure-Survival Relationship
2.4. Exposure-Toxicity Relationship
3. Discussion
4. Materials and Methods
4.1. Participants
4.2. Treatment
4.3. Pharmacokinetic Measurements
4.4. PD-L1 Expression Analysis
4.5. Study Endpoints
4.6. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Characteristics | n = 81 |
Demographic data | |
Sex, n (%) | |
Male | 49 (60) |
Female | 32 (40) |
Age (years) | 65.0 (57.0–69.0) |
Body weight (kg) | 69.0 (62.0–78.0) |
BMI (kg/m2) | 23.7 (21.7–26.5) |
Lean body mass (kg) | 51.7 (41.3–57.2) |
ECOG performance status, n (%) | |
0–1 | 45 (56) |
2 | 36 (44) |
Corticosteroids therapy at nivolumab initiation, n (%) | 14 (17) |
Corticosteroids daily dose (mg) | 20 (10–25) |
Disease characteristics | |
Histological tumor type, n (%) | |
Adenocarcinoma | 52 (64) |
Squamous cell carcinoma | 16 (20) |
Other | 13 (16) |
Number of previous treatment line, n (%) | |
1 | 58 (72) |
2 | 13 (16) |
≥3 | 10 (12) |
Metastasis, n (%) | |
Synchronous | 55 (68) |
Metachronous | 26 (32) |
Number of extrathoracic metastatic sites, n (%) | |
0 | 20 (25) |
1 | 29 (36) |
2 | 17 (21) |
≥3 | 15 (18) |
Cerebral metastasis, n (%) | |
Yes | 20 (25) |
No | 61 (75) |
Tumor cells PD-L1 expression (%) | 5 (0–28) |
Baseline Biological data | |
Hemoglobin (g/dL) (n = 80) | 12.2 (11.2–13.3) |
Platelets (×109/L) (n = 80) | 244 (199–322) |
Lymphocytes (×109/L) (n = 74) | 1.18 (0.85–1.72) |
Neutrophils (×109/L) (n = 80) | 5.31 (3.89–6.84) |
NLR (n = 74) | 4.31 (2.99–5.67) |
IgG (UI/mL) (n = 77) | 10.2 (7.6–13.2) |
PAL (UI/L) (n = 78) | 87 (71–109) |
AST (UI/L) (n = 78) | 25 (21–31) |
ALT (UI/L) (n = 78) | 22 (18–35) |
Total bilirubin (µmol/L) (n = 79) | 5.9 (4.3–7.1) |
Albumin (g/L) (n = 81) | 38 (34–42) |
CRP (mg/L) (n = 77) | 11.2 (3.4–31.9) |
Creatinine (µmol/L) (n = 81) | 78 (64–90) |
Univariate | Multivariate | ||
---|---|---|---|
Linear regression coefficient estimate (95% CI) | p-value | p-value | |
Age (year) (n = 75) | 0.016 (−0.084; 0.117) | 0.746 | |
Age > 70 years old (n = 75) | 1.54 (−1.77; 4.85) | 0.357 | |
Sex (male) (n=75) | −2.48 (−5.25; 0.28) | 0.0777 | 0.36 |
Total body weight (kg) (n = 75) | 0.146 (0.045; 0.247) | 0.005 | |
BMI (kg.m-2) (n = 75) | 0.78 (0.48; 1.09) | 0.0000016 | <0.0001 |
Lean body mass (kg) (n = 75) | 0.012 (−0.13; 0.15) | 0.862 | |
CRP (mg/L) (n = 72) | −0.054 (−0.094; −0.014) | 0.0089 | 0.69 |
Albumin (g/L) (n = 75) | 0.42 (0.12; 0.72) | 0.0068 | 0.10 |
IgG (UI) (n = 71) | −0.277 (−0.661; 0.108) | 0.156 | |
AST (UI) (n = 72) | −0.043 (−0.159; 0.074) | 0.47 | |
ALT(UI) (n = 72) | 0.044 (−0.050;0.138) | 0.352 | |
Creatinine clearance (mL/min) a | 0.019 (−0.025; 0.064) | 0.388 | |
PD-L1 expression | −0.0163 (−0.0643; 0.0318) | 0.498 | |
Stage III vs stage IV (reference = stage III) | −1.571 (−4.882; 1.740) | 0.348 | |
Adenocarcinoma vs SCC | −2.036 (−5.578; 1.506) | 0.255 | |
Cerebral metastasis (reference = no) | −3.946 (0.873; 7.018) | 0.013 | 0.145 |
Baseline use of corticosteroids | 2.1 (−1.55; 5.76) | 0.255 |
Univariate Model HR (95%CI) | p-Value | Multivariate Model HR (95%CI) (n = 46) | p-value | |
---|---|---|---|---|
Risk of death | ||||
Cmin D14 ≤median (n = 62) | 1.03 (0.55–1.96) | 0.9145 | ||
Cmin D28 ≤median (n = 53) | 0.51 (0.24–1.09) | 0.0786 | 1.37 (0.44-4.32) | 0.586 |
ECOG Performance Status (n = 64) | 2.06 (1.28–3.30) | 0.0034 | 1.75 (1.86–3.57) | 0.122 |
Number of metastasis (n = 64) | 1.04 (0.80–1.35) | 0.7987 | ||
NLR > median (n = 58) | 2.38 (1.05–5.55) | 0.0036 | 1.82 (0.74–4.54) | 0.189 |
PD-L1 > 5% (n = 37) a | 0.43 (0.18–1.02) | 0.055 | ||
Baseline use of corticosteroids | 2.62 (1.29–5.31) | 0.008 | 6.29 (1.46–27.08) | 0.013 |
Risk of progression | ||||
Cmin D14 ≤ median (n = 65) | 1.14 (0.66–1.96) | 0.646 | ||
Cmin D28 ≤ median (n = 55) | 0.68 (0.37–1.27) | 0.223 | 1.30 (0.49–3.39) | 0.59 |
ECOG Performance Status (n = 67) | 1.97 (1.28–3.02) | 0.023 | 1.85 (1.02–3.38) | 0.043 |
Number of metastasis (n = 67) | 1.09 (0.87–1.37) | 0.452 | 1.14 (0.70–1.88) | 0.58 |
NLR > median (n = 60) | 1.82 (1.02–3.22) | 0.042 | ||
PD-L1 > 5% (n = 38) a | 0.44 (0.20–0.96) | 0.041 | ||
Baseline use of corticosteroids | 2.51 (1.30–4.89) | 0.008 | 8.08 [1.78–36.62) | 0.007 |
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Bellesoeur, A.; Ollier, E.; Allard, M.; Hirsch, L.; Boudou-Rouquette, P.; Arrondeau, J.; Thomas-Schoemann, A.; Tiako, M.; Khoudour, N.; Chapron, J.; et al. Is there an Exposure–Response Relationship for Nivolumab in Real-World NSCLC Patients? Cancers 2019, 11, 1784. https://doi.org/10.3390/cancers11111784
Bellesoeur A, Ollier E, Allard M, Hirsch L, Boudou-Rouquette P, Arrondeau J, Thomas-Schoemann A, Tiako M, Khoudour N, Chapron J, et al. Is there an Exposure–Response Relationship for Nivolumab in Real-World NSCLC Patients? Cancers. 2019; 11(11):1784. https://doi.org/10.3390/cancers11111784
Chicago/Turabian StyleBellesoeur, Audrey, Edouard Ollier, Marie Allard, Laure Hirsch, Pascaline Boudou-Rouquette, Jennifer Arrondeau, Audrey Thomas-Schoemann, Manuela Tiako, Nihel Khoudour, Jeanne Chapron, and et al. 2019. "Is there an Exposure–Response Relationship for Nivolumab in Real-World NSCLC Patients?" Cancers 11, no. 11: 1784. https://doi.org/10.3390/cancers11111784